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Annelien Els Student number 1997269772Mini-dissertation submitted in partial fulfilment of the requirements for the degree Magister of Science in Dietetics (M.Sc. Dietetics)
In the
FACULTY OF HEALTH SCIENCE
DEPARTMENT OF NUTRITION AND DIETETICS SCHOOL OF ALLIED HEALTH PROFESSIONS
UNIVERSITY OF THE FREE STATE BLOEMFONTEIN
SOUTH AFRICA
January 2014
Study leader: Dr. V.L. van den Berg Co-study leader: Prof. C.M. Walsh
ii
DDEECCLLAARRAATTIIOONN
I hereby declare that the work submitted in this document is my independent effort. Contributions from other researchers are appropriately referenced. I further declare that this work is submitted for the first time at University of the Free State towards a Magister degree and that it has never been submitted to any other university or faculty.
I hereby cede copyright of this work in favour of the University of the Free State.
A
AnnnneelliieennEEllss 3
iii
AACCKKNNOOWWLLEEDDGGEEMMEENNTTSS
I wish to thank the following people for their support and contributions:
My study leader, Dr. V.L. van den Berg and co-study leader, Prof. C.M. Walsh at the Department of Nutrition and Dietetics, University of the Free State for their expert supervision and contributions;
Nestlé Health Science in South Africa for allowing me the time to complete this research project;
iv
TTAABBLLEEOOFFCCOONNTTEENNTTSS
GLOSSARY OF TERMS Page 1
LIST OF ABBREVIATIONS Page 4
LIST OF TABLES Page 6
LIST OF FIGURES Page 7
CHAPTER 1: PROTOCOL Page 8
1.1 Introduction 8
1.1.1 Rationale for the study 11
1.1.2 Aim of the study 12
1.1.3 Objectives 12
1.2 Methods and design 12
1.2.1 Study design 12
1.2.2 Criteria for selecting studies 12
1.2.2.1 Inclusion criteria 13
1.2.2.2 Exclusion criteria 14
1.2.3 Identification of eligible studies and data extraction 14
1.2.3.1 Search strategy, screening and review process 14
1.2.3.2 Quality assessment 15
1.2.3.3 Data extraction 16
1.2.4 Data analysis 16
1.3 Ethics and communication 17
1.3.1 Ethics 17
1.3.2 Reporting and implementation 17
1.4 Logistics 17
1.4.1 Timeline 17
1.4.2 Budget 18
1.5 Structure of dissertation 18
1.6 Reference list 19
CHAPTER 2: LITERATURE REVIEW Page 22
v
2.2 Metabolic syndrome 25
2.2.1 Underlying disorders and manifestations 25
2.2.1.1 Insulin resistance and hyperinsulinaemia 27
2.2.1.2 Glucose intolerance 28
2.2.1.3 Hepatic complications of the metabolic syndrome 29
2.2.1.4 Hypertension 29
2.2.1.5 Other manifestations 30
2.2.2 Management 31
2.3 Obesity 31
2.3.1 Causes of obesity 31
2.3.1.1 Neuro-hormonal control of body weight 32
2.3.1.2 Environmental control of body weight 34
2.3.1.3 Genetic factors 34
2.3.2 Management 35
2.4 Non-alcoholic fatty liver disease 35
2.4.1 Clinical presentation and diagnosis 36
2.4.2 Pathophysiology 36
2.4.3 Management 36
2.5 Weight management 37
2.5.1 Approaches to weight management 37
2.5.1.1 Dietary intervention 38
2.5.1.2 Physical activity 41
2.5.1.3 Very low calorie diets 41
2.5.1.4 Behaviour modification 42
2.5.1.5 Pharmacotherapy 43
2.5.1.6 Bariatric surgery 44
2.6 Bariatric surgery 44
2.6.1 Surgical technique 45
2.6.1.1 Adjustable gastric band 46
2.6.1.2 Roux-en-Y gastric bypass 46
2.6.1.3 Sleeve gastrectomy 46
2.6.1.4 Biliopancreatic diversion and duodenal switch 46
2.6.2 Effectiveness 46
2.6.3 Mechanism of action 49
2.6.3.1 Changes to neuro-hormonal control of energy balance 49
2.6.3.2 Changes in microbiota 49
2.6.4 Hepatomegaly as a challenge to performing bariatric surgery 49
2.6.5 Morbidity and mortality 50
vi
2.6.7 Very low calorie diets and bariatric surgery 53
2.7 Conclusion 54
2.8 Reference list 55
CHAPTER 3: SYSTEMATIC REVIEW Page 64
3.1 Original article 64 3.1.1 Abstract 64 3.1.2 Introduction 66 3.1.3 Methods 68 3.1.4 Results 72 3.1.5 Discussion 82
3.1.6 Conclusion and Recommendations 85
3.1.7 Conflict of Interest 86
3.1.8 Reference list 86
3.2 Article prepared for publication submission 90
3.2.1 Abstract 91
3.2.2 Introduction 92
3.2.3 Methods 92
3.2.4 Results 92
3.2.5 Discussion 95
3.2.6 Conclusion and Recommendations 96
3.2.7 Conflict of Interest 97
3.2.8 Reference list 97
3.2.9 Tables and Images 100
APPENDIX Page 104
Appendix A Draft quality assessment form 105
Appendix B Draft screening and data extraction form 106
Appendix C Draft data collection and data summary tables 114
Appendix D Modified Quality Assessment from 115
Appendix E Obesity Surgery: Instructions for authors 116
Appendix F Title page prepared for journal submission 129
SUMMARY Page 130
1
GGLLOOSSSSAARRYYOOFFTTEERRMMSS
Abdominal fat (Intra-abdominal fat)
Fat tissue deposited internally in the abdominal cavity around the abdominal organs.
Adjustable gastric banding
A surgical procedure to reduce stomach size by placement of an inflatable device around the top portion of the stomach.
Android obesity See central obesity.
Bariatric surgery
Surgery performed on the stomach and/or intestines to facilitate weight loss.
Biliopancreatic diversion
A gastric bypass procedure involving removal of the lower portion of the stomach.
Biliopancreatic diversion with duodenal switch
Biliopancreatic diversion in which the pylorus is left intact.
Body mass index
A weight-for-height index used to classify weight status. The body mass index is calculated by dividing weight in kilogram by height in meters squared; and is interpreted in the context of underweight, normal weight, overweight and obese.
Central obesity
A form of obesity in which fat is localized around the waist area; when obesity is accompanied by an increased waist circumference.
Computed tomography
Radiographic procedure in which a three-dimensional image of a body structure is constructed from a series of plane cross-sectional images made along an axis with the use of a computer.
2
Hepatic steatosis (Fatty liver) The accumulation of fat in liver cells.
Hepatomegaly
An abnormally enlarged liver.
Insulin resistance
A decreased responsiveness to the action of insulin.
Laparoscopic surgery
A surgical technique that makes use of multiple small incisions through which surgical instruments and a camera is inserted.
Low calorie diet
A restricted energy diet that limits daily energy intake to 800-1100 kilocalories (3300-5000 kilojoules) per day.
Magnetic resonance imaging
A radiology procedure in which a nuclear magnetic resonance spectrometer is used to produce an electronic image of a molecular structure.
Metabolic syndrome
The existence of a cluster of inter-connected metabolic disturbances which may include obesity, insulin resistance, glucose intolerance, dyslipidaemia, and hypertension.
Non-alcoholic fatty liver disease
A group of liver abnormalities defined by excessive fat accumulation in the liver in individuals who do not consume excessive amounts of alcohol.
Obesity
3
Proximal gastric bypass
Surgery combining the creation of a small stomach pouch to restrict food intake and construction of bypasses of the duodenum and other segments of the small intestine.
Roux-en-Y gastric bypass
A surgical procedure involving creation of a small stomach pouch and bypassing parts of the small intestine.
Spectroscopy
An imaging method that provides information about cellular activity.
Sleeve gastrectomy
A gastric bypass procedure in which stomach size is permanently restricted.
Very low calorie diet
A diet consisting of liquid formulations used to replace food intake, supplying 800 kilocalories (3300 kilojoules) or less per day.
Visceral fat See abdominal fat
4
LLIISSTTOOFFAABBBBRREEVVIIAATTIIOONNSS
2hPG Two hour plasma glucose
β Beta
A1C Glycated haemoglobin
AACE American Association of Clinical Endocrinology
ACP American Chest Physicians
ADA Academy of Nutrition and Dietetics (previously known as the
American Dietetic Association
AGB Adjustable gastric banding
AHA American Heart Association
ALT Alanine aminotransferase
AST Aspartate aminotransferase
BMI Body mass index
BPD Biliopancreatic diversion
CCK Cholecystokinin
CHO Carbohydrate
cm centimeter
CT Computed tomography
DNA Deoxyribonucleic acid
ERAS Enhanced recovery after surgery
FDA Food and drug administration
FFA Free fatty acid
FPG Fasting plasma glucose
g gram
GIP Gastric inhibitory polypeptide
GLP-1 Glucagon-like peptide 1
HDL High density lipoprotein
ICU Intensive care unit
IDF International Diabetes Federation
IFG Impaired fasting glucose
IGT Impaired glucose tolerance
IL-6 Interleukin-6
kcal kilocalorie
kg kilogramme
5
L liter
LCD Low calorie diet
LDL Low density lipoprotein
m meter
m2 square meter
MC4R Melanocortin 4 receptor
mg/dl milligram per deciliter
ml milliliter
mmol/l millimoles per litre
MRI Magnetic resonance imaging
NAFLD Non-alcoholic fatty liver disease
NASH Non-alcoholic steatohepatitis
NCEP:ATPIII National Cholesterol Education Program Adult Treatment Panel III
NHBLI National Heart, Lung and Blood Institute
OGTT Oral glucose tolerance test
RCT Randomized controlled trial
RYGB Roux-en-Y gastric bypass
SG Sleeve gastrectomy
TG Triglycerides
TNF-α Tumour necrosis factor- alpha
VBG Vertical banded gastroplasty
VLCD Very low calorie diet
VLDL Very low density lipoprotein
6
LLIISSTTOOFFTTAABBLLEESS
List of Tables Page
Table 2.1. Classification of body mass index and central obesity 24
Table 2.2. Health outcomes associated with obesity 24
Table 2.3. Metabolic syndrome definitions 26
Table 2.4. Diagnostic criteria for diabetes-related conditions 29
Table 2.5. Neuro-hormonal control of body weight through the action of adipokines and enterokines
33 Table 2.6. Risk of developing micronutrient deficiencies after different
bariatric surgery procedures
52
Table 3.1. Inclusion and exclusion criteria 70
Table 3.2. Summary of studies excluded at level two screening 74
Table 3.3. Study characteristics of included trials as reported in included publications
77 Table 3.4. Results of included trials on reduction in liver volume and liver
fat
7
LLIISSTTOOFFFFIIGGUURREESS
List of Figures Page
Figure 1. A simplified model of the metabolic syndrome 30
Figure 2. Schematic representation of commonly performed bariatric procedures
48 Figure 3. Flow chart representing the search, screening and selection of
studies
8
C CHHAAPPTTEERR11::PPRROOTTOOCCOOLL C Chhaapptteerr11pprreesseennttsstthheepprroottooccoolltthhaattwwaassuusseeddaassaaffrraammeewwoorrkkttooeexxeeccuutteetthheerreesseeaarrcchh.. 1 GGG 1.1 IntroductionObesity is the most prevalent metabolic disease world-wide and has been declared a global epidemic affecting both developed and developing countries (Tsigos et al., 2008:106). According to the World Health Organization (WHO), obesity is classified by body mass index (BMI) which is calculated as body weight in kilogramme (kg) divided by height in meter (m) squared. In adults over 18 years of age, obesity is defined as BMI ≥ 30 kg/m2 (WHO, 2006: online).
Obesity-related health risks include a variety of complications such as metabolic disturbances (insulin resistance, type 2 diabetes mellitus, dyslipidaemia); cardiovascular disorders (hypertension, coronary heart disease, stroke); respiratory disease (asthma, sleep apnoea); hepatic disease (non-alcoholic fatty liver disease and non-(non-alcoholic steatohepatitis); cancer; and reproductive health problems (Tsigos et al., 2008:109). In addition, obesity may also increase the risk associated with surgical procedures, leading to increased perioperative morbidity and mortality (Bamgbade et al., 2007:556).
The European Clinical Practise Guidelines for the management of obesity in adults (Tsigos et al., 2008:106-116) identify obesity management as a complex process including factors such as diet, cognitive behavioural therapy, physical activity, psychological support, pharmacological treatment and surgery. Of these, surgery has been identified as the most effective treatment for sustained long-term weight loss, improvement in co-morbidities and decreased overall mortality (Tsigos et al., 2008:2113; Snow et al., 2005: 528). Surgery reduces the incidence and severity of co-morbidities including type 2 diabetes mellitus, hypertension, dyslipidaemia and obstructive sleep apnoea (Buchwald et al., 2004:1724). As such, bariatric surgery is a popular treatment modality for obesity, which however is currently reserved only for those with a BMI ≥ 40 kg/m2, or with BMI > 35 kg/m2 and significant co-morbidities who failed previous dietary attempts to effective weight loss (SAGES, 2010: online).
Though associated with treatment success, the surgical procedure constitutes only one part of the comprehensive bariatric approach in which greatest success is achieved in patients who are physically and mentally well prepared, and who are able to comply with a long-term monitoring
9
protocol. Pre- and postoperative follow-up and support is essential for optimal outcome, and patient education is important to ensure that patients are prepared to comply with permanent life-style changes (OPTIFAST Pre-Operative protocol: online).
Tsigos et al. (2008:113) classify common bariatric surgery techniques by method of action:
Restrictive procedures (food limitation), such as adjustable gastric banding , proximal gastric bypass and sleeve gastrectomy;
Absorption limiting procedures, such as biliopancreatic diversion; and
Combined techniques, such as biliopancreatic diversion with duodenal switch and Roux-en-Y gastric bypass.
Though expected average weight loss and long term maintenance of weight loss is best following procedures such as biliopancreatic diversion and gastric bypass, these procedures are also associated with increased technical complexity and nutritional risk (Tsigos et al., 2008:113).
Although the less invasive use of laparoscopic technique is preferred (Tsigos et al., 2008:113), excessive intra-abdominal fat and increased liver volume, associated with hepatic steatosis, complicate the procedure and increase surgical difficulty. Excessive intra-abdominal fat and hepatomegaly are most often seen in patients with central obesity, metabolic disorders and in the super-obese (BMI > 50 kg/m2). An enlarged left lobe of the liver obscures anatomical markers while traction of a large fatty liver may cause liver trauma with increased risk of bleeding. Large liver and excessive intra-abdominal fat reduces operating space and exposure (OPTIFAST Pre-Operative protocol: online). These difficulties explain why enlarged liver size is the most common reason for conversion from laparoscopic to open procedures (Schwartz et al., 2003:734; O’Brien et al., 2002:652;). In comparison to laparoscopic procedures, open surgery is associated with increased blood loss, longer intensive care unit (ICU) and hospital stay, risk for developing incisional hernia, as well as delayed recovery time before being able to resume daily activities of living (Colquitt et al., 2009:28; Nguyen and Wolfe, 2002:86).
Preoperative strategies to promote weight loss and reduce liver volume can therefore contribute to increased safety of surgery in obese patients undergoing bariatric surgery, in particular by reducing the likelihood of having to convert from laparoscopic to an open procedure. By, Preoperative weight loss can decrease operating time by decreasing surgical complexity (Dambrauskas et al., 2010:46) and reduce the incidence of postoperative complications (Van Nieuwenhove et al., 2011:1300).
10
Restricted energy diets, and very low calorie diets (VLCDs) in particular, have been used successfully in a number of studies to reduce weight, abdominal fat, liver size and liver fat content in the preoperative phase of bariatric surgery (Van Nieuwenhove et al., 2011: 1300-1305; Edholm et al., 2011:345-350; Colles et al., 2006:304-311; Lewis et al., 2006:697-701; Fris, 2004:1165-1170). VLCDs are defined by the Academy of Nutrition and Dietetics (previously known as the American Dietetic Association) (ADA) as liquid formulations used as exclusive food source for a period of active weight loss (thus designed to totally replace food intake), supplying a maximum of 800 kilocalories (kcal) or 6-10 kcal per kg body weight per day (equal to a maximum of 3300 kilojoules (kJ) per day). VLCDs are enriched with high biologic value protein and provide at least 100% of the daily value of essential vitamins and minerals (ADA, 2009:335). The definition for low calorie diets (LCDs) are not as clearly described in literature as that of VLDCs, and generally refer to restricted energy diets designed to achieve an energy deficit of 500-1000 kcal per day (ADA, 2002:1150); or 2090-4180 kJ per day. Similar to VLCDs, LCDs may also be in the form of liquid meal replacements used prior to bariatric surgery, and typical LCD will provide 800-1100 kcal (3300-4600 kJ) per day (Edholm et al., 2011:346). For the purpose of this review, LCDs will refer to meal replacement diets providing 800-1100 kcal (3300-4600 kJ)per day; and VLCDs will refer to meal replacement diets providing <800 kcal (3300 kJ) per day.
As a general strategy to weight loss, VLCDs may be appropriate to achieve weight loss of 5-15% of initial body weight over a period of 12-16 weeks, however concern exists in regard to weight-loss maintenance which seems to be no more successful than for traditional low energy diets (ADA, 2009:336).
The use of LCDs and VLCDs in bariatric surgery as part of preoperative management seems to be successful (Van Nieuwenhove et al., 2011: 1300-1305; Edholm et al., 2011:345-350; Colles et al., 2006:304-311; Lewis et al., 2006:697-701; Fris, 2004:1165-1170). The use thereof for different periods of preoperative duration may reduce intra-abdominal fat and liver fat content resulting in reduced liver size, therefore possibly incurring benefits for both the patient (due to improved outcomes) and the surgeon (due to reduced technical difficulty). Studies conducted to date have made use of commercial restricted energy diet products such as Optifast® VLCD (Nestlé Health Science, Switzerland) and Modifast® LCD (Inpolin AB, Sweden) for various preoperative periods ranging from 2-12 weeks. Positive outcomes on visceral and subcutaneous adipose tissue, liver volume, liver fat content and patient outcome are reported by individual studies but concerns exist in regard to increased cost and patient discomfort (Van Nieuwenhove et al., 2011: 1300-1305;
11
Edholm et al., 2011:345-350; Colles et al., 2006:304-311; Lewis et al., 2006:697-701; Fris, 2004:1165-1170). Further concerns are related to increased morbidity due to performing surgery on a catabolic patient (Gustafsson et al., 2011:571), even though earlier reports could not establish a link between preoperative VLCDs and poor wound healing or compromized immune function. No systematic review and/or meta-analysis to assess the benefits of preoperative LCDs and VLCDs in bariatric surgery patients have been published to date.
Furthermore, it is unclear what the optimal period for preoperative use of restricted energy diet programmes is since patient compliance and acceptability may be influenced by longer duration of use. Individual studies report outcomes based on durations of two weeks, four weeks, six weeks and 12 weeks (Van Nieuwenhove et al., 2011: 1300-1305; Edholm et al., 2011:345-350; Colles et al., 2006:304-311; Lewis et al., 2006:697-701; Fris, 2004:1165-1170). A study by Colles et al. (2006:304-311) suggested an ideal duration of six weeks, minimum two weeks, to achieve optimal reduction in liver volume.
The need therefore exist to conduct a systematic review and meta-analysis to explore the benefits of using a preoperative restricted energy diet protocol to reduce abdominal fat, liver size and liver fat content in obese patients scheduled for bariatric surgery. Before this practise can be considered as standard procedure, convincing evidence is needed to show that a clinically relevant reduction in liver size can be achieved in a time period that does not influence patient compliance and acceptance.
1.1.1 Rationale for the study
Excessive intra-abdominal fat and increased liver volume associated with hepatic steatosis increase surgical complexity of bariatric procedures due to obstruction of anatomical markers, reduced operating space and increased trauma with liver retraction (OPTIFAST Pre-Operative protocol: online). Hepatomegaly is the most common reason for converting from laparoscopic to open procedures (Schwartz et al., 2003:734; O’Brien et al., 2002:652), and is estimated to increase surgical difficulty in 10-20% of cases (Colles et al., 2006:304). These factors contribute to increased postoperative complications. Restricted energy diets (including both LCDs and VLCDs) have been used successfully in a number of individual studies to achieve significant reduction in liver volume and fat content in the preoperative phase of bariatric surgery (Van Nieuwenhove et al., 2011: 1300-1305; Edholm et al., 2011:345-350; Colles et al., 2006:304-311; Lewis et al., 2006:697-701; Fris,
12
2004:1165-1170). Convincing data based on a systematic review and meta-analysis is however lacking.
1.1.2 Aim of the study
The aim of the study is to review clinical trials conducted on the effect of preoperative restricted energy diets on hepatic steatosis and liver volume in adult obese patients scheduled for bariatric surgery; and to critically appraise the methods and findings of these trials by means of a systematic review. If feasible, a meta-analysis will be performed to quantify the outcomes.
1.1.3 Objectives
The primary objective of this review is to summarise outcomes on reductions in hepatic steatosis and liver volume following a preoperative commercial meal replacement restricted energy diet in adult obese bariatric surgery patients. The secondary objectives are to
(i) identify the optimal time period of LCDs and VLCDs to achieve clinically relevant reductions; (ii) identify if VLCDs are associated with better outcome compared to LCDs; and
(iii) identify the effect of restricted energy diets on incidence of postoperative complications, surgical difficulty and operating time.
1.2 Methods and design
1.2.1 Study design
A systematic review of published clinical trials will be performed to investigate the effect of commercial preoperative restricted energy diets used as meal replacements on hepatic steatosis and liver volume in adult obese patients undergoing bariatric surgery; and/or reporting on operative outcomes. If appropriate, a meta-analysis will be performed.
1.2.2 Criteria for selecting studies
The following inclusion and exclusion criteria will be used to identify all relevant studies. In order to ensure that all possible studies are included in this review, broad inclusion criteria with regard to the study design will be used.
13
1.2.2.1 Inclusion criteria
i. Study design:
All relevant studies published from January 1980 to December 2012 in peer-reviewed journals will be included in this review. Randomized and non-randomized trials will be included since the number of studies conducted as randomized controlled trials may be limited due to the small amount of research done on this topic. Although randomized controlled trials are considered the gold standard in assessing the effects of an intervention, trials of different study designs will be included to ensure a sufficient study sample. If appropriate, data obtained from randomized trials will be interpreted separately.
ii. Population:
Obese (BMI ≥ 30 kg/m2) adults (≥ 18 years) scheduled for bariatric surgery who participated in trials evaluating the effect of preoperative LCDs and VLCDs on operative outcomes (although bariatric surgery is usually reserved for those with a BMI ≥ 35 kg/m2, it may also be performed on those with a lower BMI with significant co-morbidities)
iii. Intervention:
All studies designed to evaluate the impact of preoperative restricted energy diets (LCDs and VLCDs, which for the purpose of this review, will refer to commercial meal replacement diets providing 800-1100 kcal (300-4600 kJ) per day in the case of LCDs, and meal replacement diets providing <800 kcal (3300 kJ) per day in the case of VLCDs) in obese individuals scheduled for bariatric surgery will be included. Only studies evaluating the effect of restricted energy diets applied for a time period of two to 12 weeks preoperatively will be included.
iv. Outcome measures:
Outcome measures to achieve primary and secondary objectives are as follows:
Primary outcome variables: measurement criteria that indicate reduction in liver size (as measured by ultrasound and/or whole-body imaging and/or magnetic resonance imaging and/or manual segmentation) and liver fat content (as measured by spectroscopy); and Secondary outcome variables on measurement criteria related to intra-operative factors
including operating time, blood loss, and surgical difficulty/complexity; postoperative complications; and patient compliance (adherence and/or acceptability).
14
1.2.2.2 Exclusion criteria:
The following research studies will be excluded:
Studies reporting on the effects of LDCs and VLCDs in non-obese populations;
Studies reporting on the effects of LDCs and VLCDs in populations other than those scheduled for bariatric surgery;
Studies reporting on traditional LCDs and VLCDs such as a food based self-selection diet; Studies published outside of the stipulated time period; and
Studies that include patients younger than 18 years of age.
Although the language of the publication will not serve as a means for exclusion, translation might not be viable within the time period allocated to this review. A list of all non-English studies will be listed in the report appendix. In the case of an English abstract containing sufficient scientific data, the results from the abstract will be included in the systematic review process.
1.2.3 Identification of eligible studies and data extraction
1.2.3.1 Search strategy, screening and review process
The following two-step search strategy will be applied to identify eligible studies: 1. Electronic bibliographic databases will be searched for appropriate studies; 2. Reference lists of all eligible studies will be screened for appropriate studiess.
Electronic databases will include EbscoHost (including MEDLINE, HealthSource (academic edition) and CINAHL), Cochrane (Cochrane Database of Systematic reviews, Cochrane controlled trials register), Pubmed and Science Direct.
The following search terms will be used to seek eligible studies from these databases:
[very low calorie diet(s) OR low calorie diet(s) OR low energy diet(s) OR very low energy diet(s) or restricted energy diet(s)]
AND
[bariatric surgery OR laparoscopic gastric bypass OR Roux-en-Y gastric bypass OR gastric banding OR sleeve gastrectomy OR biliopancreatic diversion]
15
[liver volume OR liver size OR liver fat OR hepatic volume OR (intra)hepatic fat OR hepatic steatosis OR liver steatosis]
AND/OR
[(post)operative complication(s) OR (post)operative outcome OR intra-operative outcome OR operating time OR blood loss OR surgical difficulty OR surgical complexity OR patient compliance OR patient adherence OR patient acceptability]
Two independent reviewers with experience in systematic reviews (the researcher and one of the study leaders), will screen all studies identified based on title, after which abstracts for eligible studies will be obtained. Full-text articles will be retrieved for all studies which adhere to the inclusion criteria. Although full-text articles are preferred for the data-extraction, abstracts which contain sufficient scientific data will also be included. All eligible studies will be evaluated and discussed by the two reviewers to ensure relevance.
A table detailing all studies excluded during the systematic search process, as well as the reason for exclusion, will be compiled.
1.2.3.2 Quality assessment
A standard assessment form will be developed to assess the quality of each included publication (see appendix A for preliminary questionnaire). The quality will be judged according to the following criteria:
Specification of target population;
Sampling method (Was the sample chosen by consecutive inclusion, or whole population?); Specification of inclusion and exclusion criteria;
Randomization criteria (How was the randomization done?);
Similarity of treatment and control group (If baseline differences occur, is this accounted for?);
Similarity in treatment other than intervention (Did co-intervention occur?);
Effect of lost to follow-up (Were withdrawals described and did they occur with similar frequency between the intervention and control groups?);
Intention to treat presentation of data (Were participants analysed according to the intervention to which they were allocated, whether they received it or not?);
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Blinding of investigators and/or data-collectors (Were outcome assessor independent from the individuals administrating/supervising the assigned intervention?).
The response options for the above criteria are as follows: yes (subdivided as criteria appropriately applied or inappropriately applied), unclear (criteria not described), and no (criteria not applied). After evaluating each study according to these criteria, all studies will be classified as:
Low risk of bias: all criteria met;
Moderate risk of bias: one or more of the criteria unclear; or High risk of bias: one or more of the criteria not met.
The results from the quality assessment will, in the case of a meta-analysis being conducted, impact on the methodological quality.
In the case of disagreement between the two reviewers on any specific aspect, a third party with expertise in the area will be consulted.
1.2.3.3 Data extraction
Data will be extracted independently by 3 reviewers using a screening and data extraction form (preliminary form attached in appendix B), and will be summarized in table format (preliminary table is attached in appendix C). If required data is not reported in the publication, an attempt will be made to contact the trial manager(s).
1.2.4 Data analysis
The results from the included studies will be evaluated according to: 1. Study design and quality;
2. Participants: type of surgery;
3. Intervention: duration of preoperative diet; and 4. Outcomes:
a. Primary outcome, namely the hepatic steatosis and liver size; and
b. Secondary outcomes, namely intra-operative factors including operating time, blood loss, surgical difficulty/complexity; postoperative complications, and patient compliance (adherence and acceptability).
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The various dietary interventions will be assessed and compared to one another according to this analysis. The impact of dietary interventions will be determined statistically if there is sufficient homogeneity across the studies with regard to the target population, intervention, comparison groups, and outcomes measured. As different dietary interventions will be assessed, the homogeneity of each type of intervention will be assessed individually.
1.3 Ethics and communication
1.3.1 Ethics
This protocol will be submitted for ethical approval to the Ethics Committee of the Faculty of Health Sciences, University of the Free State (South Africa).
The researcher undertakes an oath not to commit plagiarism. Information obtained from included studies will be adequately referenced.
1.3.2 Reporting and implementation
The final report will be compiled in the form of a scientific publication for submission to a peer reviewed scientific journal; taking into account the publisher’s submission instructions.
1.4 Logistics
1.4.1 Timeline
Estimates on the start and end dates for conducting the systematic review is as follows:
Proposal development: 01 June 2012 – 31 July 2012
Ethical approval: Before end 2012, in accordance with the meeting
schedule of the Ethical Committee
Writing of literature review: 01 January 2013 – 30 March 2013
Data search: 02 January 2013 – 30 April 2013
Analysis: 01 May 2013 – 15 July 2013
Writing of results and dissertation: 15 July 2013 – 30 August 2013
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Editing: Submission: 01 October 2013 – 31 December 2013 January 2014 1.4.2 BudgetEstimation of the cost to complete the study (all cost will be carried by the researcher): Inter-library loans; postage; on-line purchase of articles: R 800-00
Stationary: R 150-00
Printing: R 800-00
Binding: R 50-00
Total: R 1800-00
1.5 Structure of dissertation
The mini-dissertation will include the following parts: Chapter 1: Protocol (as originally planned)
Chapter 2: General literature review providing information on surgical interventions related to treatment of obesity, as well as surgical complications and the role on nutrition;
Chapter 3: Systematic review. The research publication will include a description of the systematic review process, as well as a presentation and discussion of the findings; and Appendix.
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1.6 Reference list
Academy of Nutrition and Dietetics (ADA). 2002. Position of the American Dietetic Association: Weight Management. Journal of the American Dietetic Association, 102:1145-1155.
cademy of Nutrition and Dietetics (ADA). 2009. Position of the American Dietetic Association: Weight Management. Journal of the American Dietetic Association, 109:330-346.
Bamgbade OA, Rutter TW, Nafiu OO, Dorje P. 2007. Postoperative complications in obese and nonobese patients. World Journal of Surgery, 31:556-560.
Buchwald H, Avidor Y, Braunwald E, Jensen MD, Pories W, Fahrbach K, Schoelles K. 2004. Bariatric surgery: a systematic review and meta-analysis. Journal of the American Medical Association, 292(14): 1724-1737.
Colles SL, Dixon JB, Marks P, Strauss BJ, O’Brien PE. 2006. Preoperative weight loss with a very-low-energy diet: quantition on changes in liver and abdominal fat by serial imaging. American Journal of Clinical Nutrition, 84:304-311.
Colquitt JL, Picot J, Loveman E, Clegg AJ. 2009. Surgery for obesity. Cochrane Database of Systematic Reviews, Issue 2. Art.No.: CD003641. DOI: 10.1002/14651858.CD003641.pub3.
Dambrauskas Z, Wiezer R, Campillo-Soto A, Kramer M, Van Dielen F, Maleckas A, Van Nieuwenhove Y, Jannsen I, Thorell A. 2010. The effects of short term preoperative very low calorie diet on operative outcomes after laparoscopic Roux-en-Y gastric bypass for morbid obesity. Obesity Reviews, 11(Suppl1):46.
Edholm D, Kullberg J, Haenni A, Karlsson FA, Ahlström A, Hedberg J, Ahlström H, Sundbom M. 2011. Preoperative 4-week low calorie diet reduces liver volume and intrahepatic fat, and facilitates laparoscopic gastric bypass in morbidly obese. Obesity Surgery, 21:345-350.
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Gustafsson UO, Hausel J, Thorell A, Ljungqvist O, Soop M, Nygren J. 2011. Adherence to the enhanced recovery after surgery protocol and outcomes after colorectal cancer surgery. Archives of Surgery, 146(5):571-577.
Lewis MC, Phillips ML, Slavotinek JP, Kow L, Thompson CH, Toouli J. 2006. Change in Liver size and fat content after treatment with Optifast very low calorie diet. Obesity Surgery, 16:679-701.
Nguyen NT, Wolfe BM. 2002. Laparoscopic versus open gastric bypass. Seminars in Laparoscopic Surgery, 9(2): 86-93.
O’Brien PE, Dixon JB, Brown W, Schachter LM, Chapman L, Burn AJ, Dixon ME, Scheinkestel C, Halket C, Sutherland LJ, Krin A, Baquie P. 2002. The laparoscopic adjustable gastric band (Lap-Band): a prospective study of medium-term effects on weight, health and quality of life. Obesity Surgery, 12:652-660.
Optifast VLCD Pre-operative protocol [Online]. Available from
http://www.nestlehealthscience.com.au/Nutrition-Articles/Weight-Management/~/media/Files/NHS/PDFs/WM_5_Optifast-Pre-Op-Protocol.ashx [Accessed July 9th 2012].
Society of American Gastrointestinal Endoscopic Surgeons (SAGES). 2010. Bariatric surgery: Society of American Gastrointestinal Endoscopic Surgeons guidelines for laparoscopic and conventional surgical treatment of morbid obesity [Online].
Available from
http://www.lapsurgery.com/BARIATRIC%20SURGERY/SAGES.htm#SAGES%20GUIDELINES [Accessed July 10th 2012].
Schwartz ML, Drew RL, Chazin-Caldie M. 2003. Laparoscopic Roux-en-Y gastric bypass: preoperative determinants of prolonged operative times, conversion to open gastric bypasses, and postoperative complications. Obesity Surgery, 13:734-738.
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Snow V, Barry P, Fitterman N, Qaseem A, Weiss K. 2005. Pharmacologic and surgical management of obesity in primary care: a clinical practise guideline from the American College of Physicians. Annals of Internal Medicine, 142:525-531.
Tsigos C, Hainer V, Basdevant A, Finer N, Fried M, Mathus-Vliegen E, Micic D, Maislos M, Roman G, Schutz Y, Toplak H, Zahorska-Markiewicz B. 2008. Management of obesity in adults: European clinical practise guidelines. Obesity Facts, The European Journal of Obesity, 1:106-116.
Van Nieuwenhove Y, Dambrauskas Z, Campillo-Soto A, Van Dielen F, Weizer R, Janssen I, Kramer M, Thorell A. 2011. Preoperative very low calorie diet and operative outcome after laparoscopic gastric bypass. Archives of Surgery, 146(11):1300-1305.
World Health Organization (WHO). 2006. Global database on body mass index [Online]. Available from http://apps.who.int/bmi/index.jsp?introPage=intro_3.html
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C CHHAAPPTTEERR22::LLIITTEERRAATTUURREERREEVVIIEEWW C Chhaapptteerr22iissaarreevviieewwoofflliitteerraattuurreeppeerrttaaiinniinnggttoooobbeessiittyyaannddbbaarriiaattrriiccssuurrggeerryyaasstthheemmoosstteeffffeeccttiivvee i inntteerrvveennttiioonnffoorroobbeessiittyymmaannaaggeemmeenntt.. 2 GGG 2.1 IntroductionObesity is defined by the World Health Organization (WHO) as excessive body fat accumulation that may impair health (WHO, 2013a: online). As per body mass index (BMI) classification of more than 30 kilogramme (kg) per square meter (m2), obesity currently affects 500-600 million people worldwide (International Obesity Taskforce, 2013: online). BMI definition, calculation and classification are presented in Table 2.1.
The 2010 Global Status Report on non-communicable diseases identifies obesity as a global epidemic and states that overweight and obesity contributes to 2.8 million global deaths on an annual basis (WHO, 2011:22). This is linked to the fact that excessive body fat increases the risk for various health problems (see Table 2.2.), some of which represent major causes of death and disability. Risk factors associated with obesity include coronary heart disease, ischaemic stroke, type 2 diabetes mellitus, hypertension, certain types of cancer, as well as hepatic disease (WHO, 2011:22-23; Neuschwander-Tetri, 2005:327). Many of these associated comorbidities form part of the metabolic syndrome. Metabolic syndrome is not a disease per se, but a combination of metabolic abnormalities which can present in different ways in accordance to the various components that constitute the syndrome. Obesity, particularly central obesity which is indicated by increased waist circumference, is one of the main components of the metabolic syndrome. Other components of the metabolic syndrome include insulin resistance, glucose intolerance, dyslipidaemia, and hypertension. Glucose intolerance may lead to the development of type 2 diabetes mellitus; while all components individually and in combination are risk factors for the development of cardiovascular disease (Eckel et al., 2005:1415-1417). Metabolic syndrome can also present as non-alcoholic fatty liver disease (NAFLD), sometimes referred to as the hepatic manifestation of the syndrome (Hafeez and Ahmed, 2013:2).
Given the increasing prevalence of obesity, global weight management programmes aim to reduce or maintain BMI values within normal parameters, which will also reduce manifestation of comorbidities associated with metabolic syndrome. Preventative programmes are mainly targeted at national governments, authorities and policy makers with the aim to improve dietary and lifestyle
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behaviour on a global level; while evidence-based treatment approaches to weight management guide therapeutic interventions such as therapeutic diet programmes, pharmacotherapy and bariatric surgery applied to individual cases.
Of all treatment approaches, bariatric surgery is regarded as the most successful and durable option for long-term management of obesity. Bariatric surgery is associated with a significant decrease in body weight, fat mass and BMI; improvement in insulin sensitivity; remission of type 2 diabetes mellitus; and regression of NAFLD (Mechanick et al., 2013:160; Hafeez and Ahmed, 2013:2-3). Bariatric procedures may however be complicated by NAFLD since the presence of a large, fatty liver obscures the surgical view and restricts operative access (Colles et al., 2006:304; Lewis et al. 2006:698).
In this literature review, the pathophysiology of metabolic syndrome will be briefly explained. This will be followed by an overview of obesity and non-alcoholic fatty liver disease. Weight management strategies will be briefly reviewed, with special focus on the role of bariatric surgery and how an enlarged liver complicates surgical procedures. The potential role of restricted energy diets on reducing liver size pre-bariatric surgery will also be highlighted.
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Table 2.1. Classification of body mass index and central obesity (WHO, 2013b: online; International Diabetes Federation, 2006: online).
BMI:
BMI is a weight-for-height index used to classify weight status in adults. It is calculated by dividing body weight (in kg) by the square of the height (in m).
Classification:
Central obesity:
A BMI value ≥ 30 kg/m2 together with an increased waist circumference indicates central obesity. For the identification of increased waist circumference, population and country-specific cut-off values apply. While currently there are no country-specific values for Sub-Saharan Africa, the IDF recommends using the same values as for Europides to identify increased waist circumference, namely ≥ 94 cm in males and ≥ 80 cm in females.
kg: kilogramme; m: meter; BMI: body mass index; IDF: International Diabetes Federation; cm: centimetre.
Table 2.2. Health outcomes associated with obesity (Hng and Ang, 2012:435). Type 2 diabetes mellitus
Hypertension Dyslipidemia
Cardiovascular disease Obstructive sleep apnoea
Obesity hypoventilation syndrome Cancer Gallstones Pseudotumour cerebri Osteoarthritis Infertility Urinary incontinence Gastro-esophageal reflux Non-alcoholic fatty liver disease
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2.2 Metabolic syndrome
Metabolic syndrome presents as a cluster of inter-connected metabolic disturbances. Various international organizations and expert groups have attempted to define metabolic syndrome by incorporating the different components thereof. These include (amongst others) definitions by the National Cholesterol Education Program Adult Treatment Panel III (NCEP:ATPIII), American Association of Clinical Endocrinology (AACE), International Diabetes Federation (IDF), and American Heart Association (AHA) in collaboration with National Heart, Lung and Blood Institute (NHLBI). These definitions are presented in Table 2.3. A consensus definition put forward in 2009 by a working group representing various professional organizations (Alberti et al., 2009:1640) defines metabolic syndrome as the prevalence of any three of the following:
Elevated waist circumference (according to ethnic and country-specific values);
Triglyceride level ≥ 150 milligram per decilitre (mg/dl) or 1.69 millimoles per litre (mmol/l); High density lipoprotein (HDL) cholesterol < 40 mg/dl (1.03 mmol/l) in men and < 50 mg/ dl
(1.29 mmol/l) in women;
Blood pressure reading ≥ 130/85 mmHg; Fasting glucose ≥ 100 mg/dl (5.56 mmol/l).
2.2.1 Underlying disorders and manifestations
Eckel et al. (2010:182) states that metabolic syndrome is an “outgrowth” of insulin resistance. This indicates that the individual factors which in co-existence constitutes metabolic syndrome, are all primarily caused by insulin resistance. Insulin resistance is a subnormal biologic response to insulin in which a given concentration of insulin will produce a less-than-expected biological effect.
Figure 1 is based on the current model of metabolic syndrome as explained by Eckel et al. (2005:1418-1420) and represents the main components of metabolic syndrome (insulin resistance, glucose intolerance, dyslipidaemia, hypertension and NAFLD) and how these are inter-related, with central obesity as the main starting point.
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Table 2.3. Metabolic syndrome definitions (Kassi et al., 2011:9).
National Cholesterol Education Program Adult Treatment Panel III (NCEP:ATPIII):
Any three or more of the following:
Waist circumference > 102 cm in men and > 88 cm in women; TG ≥ 150 mg/dl (1.69 mmol/l);
HDL-cholesterol < 40 mg/dl (1.03 mmol/l) in men and < 50 mg/dl (1.29 mmol/l) in women;
BP ≥ 130/85 mmHg;
Fasting glucose ≥ 100 mg/dl (5.56 mmol/l).
American Association of Clinical Endocrinology (AACE):
Impaired glucose tolerance plus two or more of the following: BMI ≥ 25 kg/m2;
TG ≥ 150 mg/dl (1.69 mmol/l) and/or HDL-cholesterol < 40 mg/dl (1.03 mmol/l) in men and < 50 mg/dl (1.29 mmol/l) in women;
BP ≥ 130/85 mmHg.
International Diabetes Federation (IDF):
Central obesity (defined by waist circumference with ethnicity-specific values#, but can be assumed if BMI > 30 kg/m2), plus two of the following:
TG ≥ 150 mg/dl (1.69 mmol/l);
HDL-cholesterol < 40 mg/dl (1.03 mmol/l) in men and < 50 mg/dl (1.29 mmol/l) in women;
BP ≥ 130/85 mmHg;
Fasting glucose ≥ 100 mg/dl (5.56 mmol/l).
American Heart Association in collaboration with National Heart, Lung and Blood Institute (AHA/NHLBI):
Any three of the following:
Waist circumference ≥ 102 cm in men, and ≥ 88 cm or greater in women; TG ≥ 150 mg/dl (1.69 mmol/l);
HDL-cholesterol < 40 mg/dl (1.03 mmol/l) in men and < 50 mg/dl (1.29 mmol/l) in women;
BP ≥ 130/85 mmHg;
Fasting glucose ≥ 100 mg/dl (5.56 mmol/l).
TG: Triglyceride; HDL: High density lipoprotein; BP: blood pressure: BMI: body mass index
#
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2.2.1.1 Insulin resistance and hyperinsulinaemia
Insulin resistance is marked by high serum insulin concentrations (hyperinsulinaemia) in association with normal or high blood glucose concentrations (Olatunbosun and Dagogo-Jack, 2013: online) in both postprandial and fasting states. In the context of metabolic syndrome, insulin resistance is strongly associated with obesity. Growing adipose cells release an overabundance of fatty acids into the circulation, and this interferes with insulin action. The various manifestations of metabolic syndrome is thus all directly or indirectly caused by insulin resistance, which is brought about by an overabundance of intra-abdominal fat (Eckel et al., 2005:1418).
Lipolysis of visceral adipose stores increases the amount of circulating fatty acids, which in turn is associated with the development of insulin resistance. The mechanism by which an increase in fatty acids cause reduced biologic response to insulin is related to modification of insulin signalling. Normal action of insulin is linked to the binding of insulin to specific insulin receptors which initiates a cascade of events: insulin receptor tyrosine kinase is activated, which leads to the phosphorylation of insulin receptor substrates. This in turn activates other pathways which eventually stimulates glucose uptake. The presence of high circulating concentrations of free fatty acids interferes with the signalling pathway, and hampers insulin-stimulated glucose uptake (Ragheb and Medhat, 2011:1). Other mechanisms by which fatty acids may impair insulin action is explained by Delarue and Magnan (2007:143-144) and involves defects created by fatty acids in glucose oxidation and in glucose transport receptors, and by an increase in fatty acid substrate availability. The latter is supported by the reciprocal metabolic relationship between glucose and fatty acid whereby increased glucose availability increases glucose oxidation and storage while inhibiting fatty acid oxidation; and fatty acid availability promotes fatty acid oxidation and storage while inhibiting glucose oxidation.
Since insulin acts as an anti-lipolytic agent, insulin resistance that develops as a result of increase fatty acid availability, creates a feedback system leading to an even higher release of fatty acids through lipolysis (Eckel et al., 2005:1418). Under normal metabolic conditions, postprandial insulin release will inhibit lipolysis of adipose tissue. When insulin resistance is present however, lipolysis is not constrained and therefor the production of fatty acids increases beyond normal circulating levels.
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2.2.1.2 Glucose intolerance
In addition to all the aforementioned effects of insulin resistance, glucose intolerance may result. This can be attributed to both a decrease in insulin sensitivity (the impaired ability of insulin to decrease glucose production by the liver and to mediate glucose uptake by tissue cells); as well as damage to insulin-producing pancreatic-beta (β) cells (Eckel et al., 2005:1420). Therefor insulin resistance may cause impaired fasting glucose and impaired glucose tolerance (both of which indicate a state of prediabetes), as well as type 2 diabetes mellitus.
Under normal metabolic circumstances, insulin that is released by pancreatic β-cells closely control blood glucose levels. A feedback-loop between insulin–sensitive tissue (such as liver and muscle) and β-cells regulate the release of insulin based on blood glucose levels and cellular demand. In case of insulin resistance, a greater insulin response is needed to maintain normal glucose levels, and hyperinsulinaemia may develop. Failure in the feedback-mechanism will cause glucose intolerance with high plasma glucose levels. In addition to increased release of insulin by pancreatic cells, hepatic clearance of insulin is also lowered in individuals who are insulin resistant, and this furthers the development of hyperinsulinaemia (Kahn et al., 2006:840-844).
Not all obese, insulin–resistant individuals develop type 2 diabetes mellitus as β-cells can compensate for decreased insulin sensitivity by increasing insulin release. However, high circulating levels of fatty acids induce a state of lipotoxicity which causes damage to pancreatic β-cells and a continued decline in β-cell function (Kahn et al., 2006:842-844). Failure of β-cells to adapt leads to a rise in postprandial and fasting plasma glucose levels, resulting in prediabetes and eventually type 2 diabetes mellitus (see diagnostic criteria for diabetes and prediabetes in Table 2.4.).
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Table 2.4. Diagnostic criteria for diabetes-related conditions (Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, 2013:S9)
Criteria for the diagnosis of diabetes:
FPG ≥ 7 mmol/l OR A1C ≥ 6.5% (adults) OR 2hPG in a 75g OGTT ≥ 11.1 mmol/l OR Random PG ≥ 11.1 mmol/l
Criteria for the diagnosis of prediabetes:
IFG: FPG = 6.1-6.9 mmol/l
IGT: 2hPG in a 75g OGTT = 7.8-11 mmol/l Prediabetes: A1C = 6-6.4%
FPG: fasting plasma glucose (no caloric intake for at least eight hours); A1C: glycated haemoglobin; 2hPG: 2 hour plasma glucose; OGTT: oral glucose tolerance test; PG: plasma glucose; IFG: impaired fasting glucose; IGT: impaired glucose tolerance
2.2.1.3 Hepatic complications of the metabolic syndrome
Fatty acids derived from lipolysis of visceral adipose tissue result in an increased flux to the splanchnic circulation, compared to lipolysis of subcutaneous fat which tend to be released into the systemic circulation. The splanchnic circulation delivers fatty acids to the liver where it either accumulates in hepatocytes as triglyceride droplets (causing NAFLD); or are secreted as very low density lipoprotein (VLDL) into the circulation. As with all other manifestations of metabolic syndrome, the process of liver steatosis is initiated by insulin resistance and the excessive release of fatty acids from visceral adipose tissue. Chronic hyperinsulinaemia, as a result of insulin resistance, impairs the release of triglycerides into circulation, causing accumulation thereof in hepatocytes. Thus, insulin resistance constantly feeds more fatty acids into the liver while simultaneously hampering the release thereof (Neuschwander-Tetri, 2005:327-328). The prevalence and treatment of NAFLD is discussed in more detail in section 2.3
2.2.1.4 Hypertension
Metabolic syndrome is also associated with development of hypertension. The relationship between blood pressure control and insulin resistance is explained mainly through (i) the action of insulin on stimulating endothelin-1 release by vascular endothelial cells, thereby causing constriction of blood vessels and hence an increase in blood pressure; and (ii) the fact that insulin stimulates renal sodium reabsorption. While the vasoconstriction effect may be lost in case of insulin resistance, the latter effect remains and leads to increase in blood pressure as a result of higher sodium concentration (Eckel et al., 2005:1420).
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2.2.1.5 Other manifestations
In addition to the effect of lipolysis of visceral adipose tissue and the resultant effects of increased fatty acids and insulin resistance, changes in adipose tissue secretions may further increase the risk of developing conditions associated with metabolic syndrome. Adipose tissue, in particular visceral fat, can be viewed as an endocrine organ which secretes various bioactive substances acting as biomarkers and biosensors. Collectively, these substances are referred to as adipokines and includes amongst others adiponectin, leptin, as well as the inflammatory mediators tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). In the presence of obesity, changes in the release of these adipokines may also contribute to the development of metabolic syndrome (that is, in addition to the metabolic effects of increased circulating fatty acids). The most notable change in adipokine release is the change in adiponectin release which is decreased in case of excessive visceral fat stores. Adiponectin functions as an insulin sensitizer, therefor hypoadiponectonemia is implicated in the development of insulin resistance and associated co-morbidities including type 2 diabetes mellitus, hypertension and cardiovascular disease (Deng and Scherer, 2010:E1-E2).
VLDL: very low density lipoprotein; TG: triglycerides; HDL: high density lipoprotein
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This explanation briefly highlights the main inter-related components of metabolic syndrome for the purpose of clarifying the context of the following sections, as in totality, the metabolic pathways involved in metabolic syndrome are much more intricate.
2.2.2 Management
The fact that insulin resistance and central obesity are regarded as the main underlying causes of metabolic syndrome motivates weight control as the key focus in management of the syndrome and its manifestations. Weight reduction has a positive impact on all components of metabolic syndrome, mainly through improvement in insulin sensitivity. The underlying mechanism appears to be a reduction in fatty acid mobilization brought about by reduction in body weight (Schenk et al., 2009:4949). Weight management is discussed in more detail in section 2.5.
2.3 Obesity
Obesity is a global epidemic which also affects a great proportion of the local population: in South Africa it is estimated that 50% of adults are currently obese. This represents 10.6% of the South African male population and 39.2% of females. High obesity figures are also found in the paediatric population. Locally, 16.2% of all boys and 23.6% of girls under the age of 18 years are obese (International Obesity Taskforce, 2013: online).
As mentioned, the WHO classification of overweight and obesity is based on BMI, while central obesity is diagnosed based on increased waist circumference (Table 1). Both overweight and obesity are major contributors to chronic diseases and present a major public health challenge, increasing healthcare cost, morbidity as well as mortality rates. Compared with normal weight individuals, obese patients require more medical treatment episodes, incur higher costs for both in-hospital and outpatient visits and also spend more on prescription medicine (Jensen et al., 2013:9). In addition, mortality rates increase with increasing degrees of overweight (WHO, 2011:23).
2.3.1 Causes of obesity
Control of whole-body energy balance is dependent on the relationship of energy intake to energy output, with a net excess intake leading to weight gain. The balance between energy intake and expenditure is controlled by a series of neuro-hormonal mechanisms, environmental components
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and genetic factors. Disturbance in one or a combination of these can decrease the ability of the body to ensure proper energy homeostasis and may result in the accumulation of body fat.
Clément (2011:S8) describes three phases in the development of obesity:
In the static phase, the individual is in energy balance and the weight is stable. Healthy body weight is defended by intrinsic control mechanisms;
In the dynamic phase, weight is gained as a result of positive energy balance. This can happen gradually as even a minor positive energy imbalance in the short term can potentially lead to persistent weight gain over time. Increased fat mass release hormonal signals which interferes with appetite control;
In the obese static phase, energy balance is regained. A new, stable (though increased) body weight is established which will, again, be vigorously defended by intrinsic regulators.
Tight regulation of the newly established weight creates the potential to add a fourth phase, the
resistance phase where increased effort is required to sustain weight loss. Rapid weight regain
following reduction of body weight is not uncommon as neuro-hormonal weight regulation by the hypothalamus favours weight increase in response to weight loss (Clement, 2011:S8).
2.3.1.1 Neuro-hormonal control of body weight
Yüksel (2009:58) describes neuro-hormonal regulation of appetite and body weight in the context of central and peripheral regulation. Hormonal and metabolic signals from the periphery are received by the central nervous system, which determine energy homeostasis within the hypothalamus. Peripheral regulators include hormonal signals by adipose tissue (adipokines, such as adiponectin and leptin) and gut hormones (enterokines, such as ghrelin, peptide YY, glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP) and cholecystokinin (CCK). Release of these bioactive substances regulates multiple aspects of energy homeostasis in a coordinated way to maintain a stable degree of body weight and whole-body energy balance. However, disturbance in one or more of these mechanisms is associated with metabolic syndrome and weight gain. For example, adiponectin levels are decreased in individuals with high proportions of visceral fat. Since adiponectin protects against development of type 2 diabetes mellitus and cardiovascular disease, low levels associated with central obesity is causally related to development of the metabolic syndrome (Kassi et al., 2011:4).
